Archive for November, 2017

Over the past five years or so, Rituximab has been the great hope for the ME/CFS community. The anecdotal stories of dramatic recoveries were beyond enticing. A successful trial could ultimately have led to the first FDA-approved drug for ME/CFS and relief for many, a huge shift in how the disease is viewed, and surely more research funding.

That unfortunately is not to be. At a talk in Norway on Nov 21st, Dr. Mella revealed that the Rituximab trial that many laid their hopes on has failed. We don’t know and won’t know the details of the failure until the paper is published next year, and Drs. Fluge and Mella talk more about the study. Dr. Mella said they provided the result so that ME/CFS patients won’t try the drug on their own.

The Norwegian trial was never by itself going to lead to FDA approval for Rituximab’s use in ME/CFS. The trial was large and rigorous enough, though, to ensure that, if successful, another trial which could lead to FDA approval would follow. The trial’s rigor had equally negative consequences; it’s hard to imagine in this funding-hampered disease that anyone is going to fund a large Rituximab trial in the future.

The main finding of the Norwegian Rituximab trial was negative but Rituximab’s ,may role in ME/CFS may not be at an end.

Rituximab may never be an FDA-approved drug for the general ME/CFS population, but its role with ME/CFS may not be over, and smaller, targeted trials are still a possibility. From the beginning, Fluge and Mella recognized the possibility of a trial failure and had a backup plan in case it failed:

However, if our selection bias in the first studies is large (i.e. if we selected out patients that are not representative of ME/CFS patients as a whole) the new study might very well turn out negative (i.e. no difference to placebo). Should that happen we would then focus our efforts on figuring out how to select the subgroup that has an immunological, rituximab-responsive disease.

Efforts to find biomarkers that identify the responders will be critical and are already underway. David Patrick of Canada reported on his use of microarrays to try and tease out which ME/CFS patients might respond to Rituximab at the 2016 IACFS/ME Conference. Nancy Klimas suggested that the Rituximab sera could very well hold the key to Rituximab’s future with ME/CFS. If autoantibodies are present in the Rituximab responders’ sera, they could be used to screen patients for future trials. She questioned whether the autoantibody patterns she’s seen in her studies might be predictive.

We know that some people with ME/CFS do respond very well to Rituximab. We’ll know more about them and the next steps Fluge and Mella will take with the drug and their other studies in early 2018.

The Rituximab Saga

The Rituximab saga began in 2004 when two oncologists noticed that Rituximab – a B-cell depleting drug often used in cancer – not only cured one of their patient’s cancer but eliminated their chronic fatigue syndrome (ME/CFS) as well. After two more ME/CFS patients responded similarly, they began their work on ME/CFS in earnest.

Several small case studies or trials ensued, all of which produced excellent results. The first one – called a preliminary case series in 2009 – reported on the three ME/CFS patients who’d improved on Rituximab. The second – a 2011 double-blinded, placebo-controlled 12 month trial of 30 patients – found Rituximab produced “major or moderate” results in 2/3rds of the participants.

The third, a 2015 open-label (the patients knew they were getting Rituximab) study, which involved giving the participants doses over a longer period of time, achieved similar results. The SF-36 scores of the major responders – about 50% of the study participants – suggested that they might be back to near normal. Not only did the trial succeed, but the trial suggested that the relapses dogging the patients from the first study could be prevented by continuing to take the drug.

The 152 person, double-blinded, placebo controlled trial that eventually resulted was spread across five hospitals in Norway. The trial had a rocky start with the Norwegian government pulling its support, but ultimately patient advocacy and patient support prevailed. The trial began in 2015 and wrapped up on time in September of this year.

Why the Trial Failed

We won’t know why the trial failed or how many people the drug worked for until the paper is published in the first half of next year but speculation is rampant.

Was “Failure”Always the Most Likely Outcome (?) – My probably minority opinion is that “failure” may have always been the most likely outcome of the study given the heterogeneity this community displays every day on Forums, Facebook and elsewhere on the internet. It may be too much to ask for many drug trials aimed at the entire ME/CFS community to succeed.

It’s important to note that Rituximab may still have a role to play in ME/CFS – just not as a drug for everyone. The key question now is how many people actually did respond to it. If a substantial number did, and a biomarker to identify them can be identified, the Rituximab trial will not go down as a failure at all.

Patient Bias? – Inadvertent patient bias – a possibility Fluge and Mella considered as the trial started – is probably the best candidate at this point. It could be that the smaller early studies inadvertently plucked out a more receptive set of patients. Once more patients were added to the mix, the effect disappeared. This is not an uncommon result in large Phase III drug trials:

“However, if our selection bias in the first studies is large (i.e. if we selected out patients that are not representative of ME/CFS patients as a whole) the new study might very well turn out negative (i.e. no difference to placebo).” Fluge and Mella

Placebo Effect? – Jorgen Jelstad put forth the intriguing idea that a high placebo effect could have doomed the drug. A similar situation appears to have doomed the Synergy trial. The Synergy compound actually did quite well but the placebo effect – possibly due to patients’ excitement about the treatment – was so strong that it was impossible to show clear separation between the effects of the drug and the placebo. Given the excitement around Rituximab, it’s possible that a similar situation has prevailed.

Endpoint – Not Disease? – It’s also possible that ME/CFS is not a single disease, but represents an endpoint or condition that can be reached in any number of different ways. Both Gulf War Illness and Lyme disease, after all, symptomatically appear to be the same as chronic fatigue syndrome but studies suggest that the three diseases are probably quite different biologically.

If different pathways exist to the same symptomatic or even cellular endpoints, then different treatment pathways will be needed. Alzheimer’s is possibly an excellent example of a complex endpoint – not a single disease – which will need a variety of approaches to resolve. Dale Bredesen MD believes that hundreds of millions of dollars and hundreds of prospective drugs have failed to make a significant dent in Alzheimer’s because the disease has been misidentified. Dale Bredesen’s studies suggest that an approach which assesses and treats a wide range of factors may actually work quite well in Alzheimer’s.

Drug Trial Failures Not Uncommon in Medicine

The ME/CFS and FM communities have recently, unfortunately, been getting acquainted with the fact that disappointments in drug trials are more common than successes. Rituximab had two small, but good, Phase II trials and seemed likely to succeed, but surprises in medical research, as Ron Davis has pointed out so many times, are common.

The next step will be determining who did respond to Rituximab and why

Jelstad’s interesting blog “The ME Rituximab Trial is Negative” (translated by Google into English) noted that Rituximab also failed in lupus despite the fact that it seemed hand-made for a B-cell associated disease. In fact, researchers were so shocked at the failure of the first large Rituximab lupus study that they immediately started another one – which subsequently bombed as well. (Despite all that, Rituximab can still work in lupus and is used in patients who haven’t responded to other treatments. )

Closer to home, two major Phase III fibromyalgia trials, one involving 10,000 patients, failed over the past year. As with ME/CFS and Rituximab, their Phase II trials had produced stellar results. Likewise, Wyller’s Clonidine trial seemed set up to reduce the “arousal” that seems manifest in this disease. Not only did the trial fail, but the drug actually made Wyller’s young ME/CFS patients worse. Medicine is full of surprises. It’s unrealistic to assume that ME/CFS won’t fall prey to some of them.

Cautionary Findings?

The result is disappointing but it’s perhaps not entirely surprising. Rumors from doctors using the drug in the U.S. on ME/CFS suggested the success rates might be lower than hoped for. If I’m reading them right, the immune B-cell studies in ME/CFS which sought to identify the issue Rituximab has addressed haven’t exactly been sterling successes.

Fluge and Mella proposed that long-lived autoantibodies or some other “slow alteration in the immune function governed by B-cells” could be causing ME/CFS. That idea was buttressed by a study finding increased rates of B-cell lymphoma in elderly ME/CFS patients.

When a German study found significantly reduced levels of muscarinic and B-adrenergic antibodies in Rituximab responders, the way forward seemed clear. Rituximab’s B-cell depleting properties were preventing B-cells from producing autoantibodies that were affecting blood flows and other processes.

The study possibly provided a cautionary note, however, when only 30% of the ME/CFS patients not given Rituximab (n=268) displayed the antibodies – a far smaller percentage than had responded in the early Rituximab trials. If those antibodies were what Rituximab was affecting – which was certainly not clear – many patients simply didn’t have them.

Meanwhile, studies that had focused on the B-cells in ME/CFS didn’t seem encouraging. Several studies prior to the Rituximab finding had not shown consistent B-cell differences between ME/CFS patients and healthy controls. A more recent found mostly modest alterations in B-cells in ME/CFS patients. Bradley’s conclusion that ME/CFS patients exhibited a “subtle tendency to autoimmunity” didn’t seem to jive with the idea that ME/CFS is a B-cell mediated autoimmune disorder”. Another study which found some B-cell abnormalities was unclear what their functional impact might be. A 2013 study simply found no differences in the B-cells of ME/CFS patients and controls.

Finally, researchers have had trouble figuring out what Rituximab was doing when it did work. Lunde’s 2016 study of ME/CFS patients receiving Rituximab found no difference in several immune measures (serum BAFF, T-Lymphocytes, T-cell activation) and just slight (but significant) reductions in immunoglobulin levels.

There’s certainly more to know about B-cells in ME/CFS – the Solve ME/CFS Initiative’s (SMCI) is funding a small study of B-cell energetics – but if B-cells are causing ME/CFS, they haven’t been giving up their secrets easily.

Enormous Impact

While the Rituximab trial failed in its main objective – to provide a drug for ME/CFS patients – there’s no denying that its impact has been enormous. Two highly creative researchers, Oystein Fluge and Olav Mella, have entered the field and say they intend to remain. Their wide-ranging efforts have and are touching on everything from autoantibodies to blood vessel functioning to metabolomics to exercise.

They and the Norwegian ME/CFS community put together the largest non-CBT/GET trial ever in ME/CFS, produced one of the largest biobanks, and created collaborations with researchers in Europe and the U.S. It proved that ME/CFS patients and their supporters from across the world will respond (Dr. Maria Gerpe reported that over 90 days, 5000 donors from more than 49 different countries contributed to the study). The Rituximab saga has provided a jolt of energy across the entire ME/CFS community.

Fluge and Mella and their supporters did the seemingly impossible: put on a large and expensive ME/CFS drug trial in a small country

Plus, the trial was not just about Rituximab. Several other studies baked into the study will add to our understanding of ME/CFS. A study examining endothelial function and skin microcirculation should tell us about blood flow issues – very possibly a key issue in ME/CFS. Their two- day exercise test should validate the highly unusual decline seen in the ability of ME/CFS patients to produce energy after exercise. Their gastrointestinal functioning test should, likewise, tell us about gut functioning in this disease.

Plus, Fluge and Mella are continuing with their cyclophosphamide trial. Cyclophosphamide has some real advantages over Rituximab. While Rituximab selectively targets B-cells, a more broadly based immune drug like cyclophosphamide may be more effective than Rituximab and has the decided benefit of being much, much cheaper. The drug is being tested in several hospitals across Norway.

Fluge and Mella have also published studies indicating breakdowns in energy production and the effects of cytokines on ME/CFS. Jorgen Jelstad pointed out that Katrina Lien’s multi-center Norwegian study is examining lactic acid production in ME/CFS. RItuximab’s early success prompted researchers to examine B-cells and autoantibodies more closely. Maureen Hanson is working with Norwegian researchers to assess the effectiveness of fecal transplants. None of this work would have been possible if Rituximab had not come to the fore.

The Rituximab saga showed that there’s no need to look to the U.S. for potential breakthroughs in this disease. Activists in smaller countries should be encouraged. Norway put the U.S. to shame in its ability to put together and fund the largest non-behavioral ME/CFS treatment trial ever. The Rituximab saga has shown that an active community and dedicated researchers in small countries can make a major impact on this disease.

We’ll know more about the next steps with Rituximab and Fluge and Mella’s work in 2018.

The Clinical Trials Picture

The loss of Rituximab puts renewed focus on Hemispherx Biopharma’s Ampligen – the other major drug possibility for ME/CFS.

Nancy Klimas at the Institute for Neuro-immune studies feels she has treatments to test now. Klimas has been chafing against federal restrictions that make it difficult to get ME/CFS clinical trials funded for years now. Neither the Research Centers grant nor, advocates take note, the Program Announcements for the ME/CFS SEP grant review panel, allow for the submission of clinical trial proposals. That means Dr. Klimas has go to rheumatology review panels to try and get her ME/CFS clinical trials funded.

Dr. Klimas reports that she’s received private funding for a phase I exploratory trial for women to start in Jan/Feb of next year and has raised half the money needed for a men’s study to hopefully begin shortly after that. (More on those later.)